Pyrazole compounds useful as protein kinase inhibitors

ABSTRACT

This invention describes novel pyrazole compounds of formula III:  
                 
 
     wherein Z 1 , Z 2 , and Z 3  are as described in the specification; Q is —S—, —O—, —N(R 4 )—, or —CH(R 6 )—; R 1  is T-Ring D, wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; and R 2  and R 2′  are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of Aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional PatentApplication 60/257,887 filed Dec. 21, 2000 and U.S. Provisional PatentApplication 60/286,949 filed Apr. 27, 2001, the contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention is in the field of medicinal chemistry andrelates to compounds that are protein kinase inhibitors, compositionscontaining such compounds and methods of use. More particularly, thisinvention relates to compounds that are inhibitors of Aurora-2 proteinkinase. The invention also relates to methods of treating diseasesassociated with protein kinases, especially diseases associated withAurora-2, such as cancer.

BACKGROUND OF THE INVENTION

[0003] The search for new therapeutic agents has been greatly aided inrecent years by better understanding of the structure of enzymes andother biomolecules associated with target diseases. One important classof enzymes that has been the subject of extensive study is the proteinkinases.

[0004] Protein kinases mediate intracellular signal transduction. Theydo this by effecting a phosphoryl transfer from a nucleosidetriphosphate to a protein acceptor that is involved in a signalingpathway. There are a number of kinases and pathways through whichextracellular and other stimuli cause a variety of cellular responses tooccur inside the cell. Examples of such stimuli include environmentaland chemical stress signals (e.g. osmotic shock, heat shock, ultravioletradiation, bacterial endotoxin, H₂O₂), cytokines (e.g. interleukin-1(IL-1) and tumor necrosis factor α (TNF-α)), and growth factors (e.g.granulocyte macrophage-colony-stimulating factor (GM-CSF), andfibroblast growth factor (FGF). An extracellular stimulus may effect oneor more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis and regulation of cell cycle.

[0005] Many diseases are associated with abnormal cellular responsestriggered by protein kinase-mediated events. These diseases includeautoimmune diseases, inflammatory diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease or hormone-related diseases.Accordingly, there has been a substantial effort in medicinal chemistryto find protein kinase inhibitors that are effective as therapeuticagents.

[0006] Aurora-2 is a serine/threonine protein kinase that has beenimplicated in human cancer, such as colon, breast and other solidtumors. This kinase is believed to be involved in proteinphosphorylation events that regulate the cell cycle. Specifically,Aurora-2 may play a role in controlling the accurate segregation ofchromosomes during mitosis. Misregulation of the cell cycle can lead tocellular proliferation and other abnormalities. In human colon cancertissue, the aurora-2 protein has been found to be overexpressed. SeeBischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J.Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997,272, 13766-13771.

[0007] Glycogen synthase kinase-3 (GSK-3) is a serine/threonine proteinkinase comprised of α and β isoforms that are each encoded by distinctgenes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim andKimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role. GSK-3 has been found tophosphorylate and modulate the activity of a number of regulatoryproteins. These proteins include glycogen synthase which is the ratelimiting enzyme necessary for glycogen synthesis, the microtubuleassociated protein Tau, the gene transcription factor β-catenin, thetranslation initiation factor e1F2B, as well as ATP citrate lyase, axin,heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These diverseprotein targets implicate GSK-3 in many aspects of cellular metabolism,proliferation, differentiation and development.

[0008] In a GSK-3 mediated pathway that is relevant for the treatment oftype II diabetes, insulin-induced signaling leads to cellular glucoseuptake and glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen,Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J.299, 123-128 (1994)]. However, in a diabetic patient where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentiallyuseful for treating diabetic patients suffering from an impairedresponse to insulin.

[0009] GSK-3 activity has also been associated with Alzheimer's disease.This disease is characterized by the well-known β-amyloid peptide andthe formation of intracellular neurofibrillary tangles. Theneurofibrillary tangles contain hyperphosphorylated Tau protein whereTau is phosphorylated on abnormal sites. GSK-3 has been shown tophosphorylate these abnormal sites in cell and animal models.Furthermore, inhibition of GSK-3 has been shown to preventhyperphosphorylation of Tau in cells [Lovestone et al., Current Biology4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)].Therefore, it is believed that GSK-3 activity may promote generation ofthe neurofibrillary tangles and the progression of Alzheimer's disease.

[0010] Another substrate of GSK-3 is β-catenin which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].

[0011] As a result of the biological importance of GSK-3, there iscurrent interest in therapeutically effective GSK-3 inhbitors. Smallmolecules that inhibit GSK-3 have recently been reported [WO 99/65897(Chiron) and WO 00/38675 (SmithKline Beecham)].

[0012] For many of the aforementioned diseases associated with abnormalGSK-3 activity, other protein kinases have also been targeted fortreating the same diseases. However, the various protein kinases oftenact through different biological pathways. For example, certainquinazoline derivatives have been reported recently as inhibitors of p38kinase (WO 00/12497 to Scios). The compounds are reported to be usefulfor treating conditions characterized by enhanced p38-α activity and/orenhanced TGF-β activity. While p38 activity has been implicated in awide variety of diseases, including diabetes, p38 kinase is not reportedto be a constituent of an insulin signaling pathway that regulatesglycogen synthesis or glucose uptake. Therefore, unlike GSK-3, p38inhibition would not be expected to enhance glycogen synthesis and/orglucose uptake.

[0013] There is a continued need to find new therapeutic agents to treathuman diseases. The protein kinases Aurora-2 and GSK-3 are especiallyattractive targets for the discovery of new therapeutics due to theirimportant roles in cancer and diabetes, respectively.

DESCRIPTION OF THE INVENTION

[0014] It has now been found that compounds of this invention andpharmaceutical compositions thereof are effective as protein kinaseinhibitors, particularly as inhibitors of Aurora-2. These compounds havethe general formula I:

[0015] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0016] Z¹ to Z⁴ are as described below;

[0017] Ring A is selected from the group consisting of:

[0018] R^(x) is T—R³ or L-Z-R³;

[0019] R^(y) is Z-R^(3′) or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms, or R^(y) and R⁸are taken together to form a fused, optionally substituted 5-7 membered,unsaturated or partially unsaturated, ring having 0-3 ring heteroatomsselected from nitrogen, oxygen, or sulfur;

[0020] Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—;

[0021] R¹ is T-(Ring D);

[0022] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0023] T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is—CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is optionallyreplaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—, —SO₂NH—,—NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

[0024] Z is a C₁₋₄ alkylidene chain;

[0025] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0026] R² and R²′ are independently selected from —R, -T—W—R⁶, or R² andR²′ are taken together with their intervening atoms to form a fused, 5-8membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

[0027] R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷ )₂;

[0028] R^(3′) is selected from -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, —OC(═O)N(R⁷)₂, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms;

[0029] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0030] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic) , —CON(R⁷)₂, or —SO₂R⁷;

[0031] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0032] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0033] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0034] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0035] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen-to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0036] R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N R⁴)₂.

[0037] As used herein, the following definitions shall apply unlessotherwise indicated. The phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted” or withthe term “(un)substituted.” Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and each substitution is independent of the other.

[0038] The term “aliphatic” as used herein means straight-chain,branched or cyclic C₁-C₁₂ hydrocarbons which are completely saturated orwhich contain one or more units of unsaturation but which are notaromatic. For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”,“alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a largermoiety includes both straight and branched chains containing one totwelve carbon atoms. The terms “alkenyl” and “alkynyl” used alone or aspart of a larger moiety shall include both straight and branched chainscontaining two to twelve carbon atoms. The term “cycloalkyl” used aloneor as part of a larger moiety shall include cyclic C₃-C₁₂ hydrocarbonswhich are completely saturated or which contain one or more units ofunsaturation, but which are not aromatic.

[0039] The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” meansalkyl, alkenyl or alkoxy, as the case may be, substituted with one ormore halogen atoms. The term “halogen” means F, Cl, Br, or I.

[0040] The term “heteroatom” means nitrogen, oxygen, or sulfur andincludes any oxidized form of nitrogen and sulfur, and the quaternizedform of any basic nitrogen. Also the term “nitrogen” includes asubstitutable nitrogen of a heterocyclic ring. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

[0041] The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic” as used herein means an aliphatic ring system having threeto fourteen members. The terms “carbocycle”, “carbocyclyl”,“carbocyclo”, or “carbocyclic” whether saturated or partiallyunsaturated, also refers to rings that are optionally substituted. Theterms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” alsoinclude aliphatic rings that are fused to one or more aromatic ornonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl,where the radical or point of attachment is on the aliphatic ring.

[0042] The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving five to fourteen members, such as phenyl, benzyl, phenethyl,1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl”also refers to rings that are optionally substituted. The term “aryl”may be used interchangeably with the term “aryl ring”. “Aryl” alsoincludes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “aryl”, as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such as in anindanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical orpoint of attachment is on the aromatic ring.

[0043] The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as usedherein includes non-aromatic ring systems having five to fourteenmembers, preferably five to ten, in which one or more ring carbons,preferably one to four, are each replaced by a heteroatom such as N, O,or S. Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl,[1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. Also included within the scope of the term “heterocyclyl”or “heterocyclic”, as it is used herein, is a group in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

[0044] The term “heteroaryl”, used alone or as part of a larger moietyas in “heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromaticring groups having five to fourteen members. Examples of heteroarylrings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl,2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl,benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl,benzooxazolyl, benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl,acridinyl, or benzoisoxazolyl. Also included within the scope of theterm “heteroaryl”, as it is used herein, is a group in which aheteroatomic ring is fused to one or more aromatic or nonaromatic ringswhere the radical or point of attachment is on the heteroaromatic ring.Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[3,4-d]pyrimidinyl. The term “heteroaryl” also refers to ringsthat are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

[0045] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like)or heteroaryl (including heteroaralkyl and heteroarylalkoxy and thelike) group may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl, heteroaryl,aralkyl, or heteroaralkyl group include a halogen, —R^(o), —OR^(o),—SR^(o), 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such asacyloxy), phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph),—CH₂(Ph), substituted —CH₂(Ph), —CH₂CH₂(Ph), substituted —CH₂CH₂(Ph),—NO₂, —CN, —N(R^(o))₂, —NR^(o)C(O)R^(o), —NR^(o)C(O)N(R^(o))₂,—NR^(o)CO₂R^(o), —NR^(o)NR^(o)C(O)R^(o), —NR^(o)NR^(o)C(O)N(R^(o))₂,—NR^(o)NR^(o)CO₂R^(o), —C(O)C(O)R^(o), —C(O)CH₂C(O)R^(o), —CO₂R^(o),—C(O)R^(o), —C(O)N(R^(o))₂, —OC(O)N(R^(o))₂, —S(O)₂R^(o), —SO₂N(R^(o))₂,—S(O)R^(o), —NR^(o)SO₂N(R^(o))₂, —NR^(o)SO₂R^(o), —C(═S)N(R^(o))₂,—C(═NH)—N(R^(o))₂, —(CH₂)_(y)NHC(O)R^(o),—(CH₂)_(y)NHC(O)CH(V—R^(o))(R^(o)); wherein R^(o) is hydrogen, asubstituted or unsubstituted aliphatic group, an unsubstitutedheteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, —O(Ph),substituted —O(Ph), —CH₂(Ph), or substituted —CH₂(Ph); y is 0-6; and Vis a linker group. Examples of substituents on the aliphatic group orthe phenyl ring of R^(o) include amino, alkylamino, dialkylamino,aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

[0046] An aliphatic group or a non-aromatic heterocyclic ring maycontain one or more substituents. Examples of suitable substituents onthe saturated carbon of an aliphatic group or of a non-aromaticheterocyclic ring include those listed above for the unsaturated carbonof an aryl or heteroaryl group and the following: ═O, ═S, ═NNHR*,═NN(R*)₂, ═N—, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*,where each R* is independently selected from hydrogen, an unsubstitutedaliphatic group or a substituted aliphatic group. Examples ofsubstituents on the aliphatic group include amino, alkylamino,dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy,haloalkoxy, or haloalkyl.

[0047] Suitable substituents on the nitrogen of a non-aromaticheterocyclic ring include —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, and—NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an aliphatic group, a substitutedaliphatic group, phenyl (Ph), substituted Ph, —O(Ph), substituted—O(Ph), CH₂(Ph), substituted CH₂(Ph), or an unsubstituted heteroaryl orheterocyclic ring. Examples of substituents on the aliphatic group orthe phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl,halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

[0048] The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are typically comprised of anatom such as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—,—C(O)NH—, or a chain of atoms, such as an alkylidene chain. Themolecular mass of a linker is typically in the range of about 14 to 200,preferably in the range of 14 to 96 with a length of up to about sixatoms. Examples of linkers include a saturated or unsaturated C₁₋₆alkylidene chain which is optionally substituted, and wherein one or twosaturated carbons of the chain are optionally replaced by —C(O)—,—C(O)C(O)—, —CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—, —NHCONH—,—OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, or —NHSO₂—.

[0049] The term “alkylidene chain” refers to an optionally substituted,straight or branched carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group.

[0050] A combination of substituents or variables is permissible only ifsuch a combination results in a stable or chemically feasible compound.A stable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

[0051] Unless otherwise stated, structures depicted herein are alsomeant to include all stereochemical forms of the structure; i.e., the Rand S configurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

[0052] Compounds of formula I or salts thereof may be formulated intocompositions. In a preferred embodiment, the composition is apharmaceutical composition. In one embodiment, the composition comprisesan amount of the protein kinase inhibitor effective to inhibit a proteinkinase, particularly Aurora-2, in a biological sample or in a patient.In another embodiment, compounds of this invention and pharmaceuticalcompositions thereof, which comprise an amount of the protein kinaseinhibitor effective to treat or prevent an Aurora-2-mediated conditionand a pharmaceutically acceptable carrier, adjuvant, or vehicle, may beformulated for administration to a patient.

[0053] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formula Ior a pharmaceutical composition thereof.

[0054] The term “Aurora-2-mediated condition” or “disease”, as usedherein, means any disease or other deleterious condition in which Aurorais known to play a role. The term “Aurora-2-mediated condition” or“disease” also means those diseases or conditions that are alleviated bytreatment with an Aurora-2 inhibitor. Such conditions include, withoutlimitation, cancer. The term “cancer” includes, but is not limited tothe following cancers: colon, breast, stomach, and ovarian.

[0055] Another aspect of the invention relates to inhibiting Aurora-2activity in a biological sample, which method comprises contacting thebiological sample with the Aurora-2 inhibitor of formula I, or acomposition thereof.

[0056] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0057] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0058] The term “GSK-3-mediated condition” or “disease”, as used herein,means any disease or other deleterious condition or state in which GSK-3is known to play a role. Such diseases or conditions include, withoutlimitation, diabetes, Alzheimer's disease, Huntington's Disease,Parkinson's Disease, AIDS-associated dementia, amyotrophic lateralsclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycetehypertrophy, reperfusion/ischemia, and baldness.

[0059] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0060] Another aspect of the invention relates to inhibiting GSK-3activity in a biological sample, which method comprises contacting thebiological sample with a GSK-3 inhibitor of formula I.

[0061] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0062] The term “pharmaceutically acceptable carrier, adjuvant, orvehicle” refers to a non-toxic carrier, adjuvant, or vehicle that may beadministered to a patient, together with a compound of this invention,and which does not destroy the pharmacological activity thereof.

[0063] The term “patient” includes human and veterinary subjects.

[0064] The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; preparations of an enzymesuitable for in vitro assay; biopsied material obtained from a mammal orextracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

[0065] The amount effective to inhibit protein kinase, for example,Aurora-2 and GSK-3, is one that measurably inhibits the kinase activitywhere compared to the activity of the enzyme in the absence of aninhibitor. Any method may be used to determine inhibition, such as, forexample, the Biological Testing Examples described below.

[0066] Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

[0067] The compositions of the present invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

[0068] Sterile injectable forms of the compositions of this inventionmay be aqueous or oleaginous suspension. These suspensions may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms mayalso be used for the purposes of formulation.

[0069] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

[0070] Alternatively, the pharmaceutical compositions of this inventionmay be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient which is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

[0071] The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

[0072] Topical application for the lower intestinal tract can beeffected in a rectal suppository formulation (see above) or in asuitable enema formulation. Topically-transdermal patches may also beused.

[0073] For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

[0074] For ophthalmic use, the pharmaceutical compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticalcompositions may be formulated in an ointment such as petrolatum.

[0075] The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

[0076] In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified diseases or disorders.

[0077] A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

[0078] Pharmaceutically acceptable prodrugs of the compounds of thisinvention include, without limitation, esters, amino acid esters,phosphate esters, metal salts and sulfonate esters.

[0079] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

[0080] Salts derived from appropriate bases include alkali metal (e.g.,sodium and potassium), alkaline earth metal (e.g., magnesium), ammoniumand N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Water or oil-soluble or dispersible products may beobtained by such quaternization.

[0081] The amount of the protein kinase inhibitor that may be combinedwith the carrier materials to produce a single dosage form will varydepending upon the patient treated and the particular mode ofadministration. Preferably, the compositions should be formulated sothat a dosage of between 0.01-100 mg/kg body weight/day of the inhibitorcan be administered to a patient receiving these compositions.

[0082] It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of the inhibitor will also depend upon the particular compound inthe composition.

[0083] Depending upon the particular protein kinase-mediated conditionto be treated or prevented, additional therapeutic agents, which arenormally administered to treat or prevent that condition, may beadministered together with the inhibitors of this invention. Forexample, in the treatment of cancer other chemotherapeutic agents orother anti-proliferative agents may be combined with the Aurora-2inhibitors of this invention to treat cancer. These agents include,without limitation, adriamycin, dexamethasone, vincristine,cyclophosphamide, fluorouracil, topotecan, taxol, interferons, andplatinum derivatives.

[0084] Other examples of agents the inhibitors of this invention mayalso be combined with include, without limitation, agents for treatingdiabetes such as insulin or insulin analogues, in injectable orinhalation form, glitazones, alpha glucosidase inhibitors, biguanides,insulin sensitizers, and sulfonyl ureas; anti-inflammatory agents suchas corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

[0085] Those additional agents may be administered separately from theprotein kinase inhibitor-containing composition, as part of a multipledosage regimen. Alternatively, those agents may be part of a singledosage form, mixed together with the protein kinase inhibitor of thisinvention in a single composition.

[0086] Compounds of this invention may exist in alternative tautomericforms, as in tautomers i and ii shown below. Unless otherwise indicated,the representation of either tautomer is meant to include the other.

[0087] Preferred R^(x) groups, when present, include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

[0088] Preferred R^(y) groups, when present, include Z-R^(3′) or anoptionally substituted group selected from C₁₋₆ aliphatic, 5-6 memberedheterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is amethylene and R^(3′) is —N(R⁴)₂, —OR, or an optionally substituted groupselected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms. PreferredR^(y) groups include 5-6 membered heteroaryl or heterocyclyl rings, suchas 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, orpiperazinyl; C₁₋₆ aliphatic, such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl; alkoxyalkylamino such as methoxyethylamino;,alkoxyalkyl such as methoxymethyl or methoxyethyl; alkyl- ordialkylamino such as ethylamino or dimethylamino; alkyl- ordialkylaminoalkoxy such as dimethylaminopropyloxy; acetamido; andoptionally substituted phenyl such as phenyl or halo-substituted phenyl.

[0089] R² and R^(2′) may be taken together to form a fused ring, thusproviding a bicyclic ring system containing a pyrazole ring. Preferredfused rings include benzo, pyrido, pyrimido, and a partially unsaturated6-membered carbocyclo ring, wherein said fused ring is optionallysubstituted. These are exemplified in the following formula I compoundshaving a pyrazole-containing bicyclic ring system:

[0090] Preferred substituents on the R²/R^(2′) fused ring include one ormore of the following: -halo, —N(R⁴)₂, —C₁₋₃ alkyl, —C₁₋₃ haloalkyl,—NO₂, —O(C₁₋₃ alkyl), —CO₂(C₁₋₃ alkyl) , —CN, —SO₂(C₁₋₃ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₃ alkyl), —NHC(O)(C₁₋₃ alkyl), —C(O)NH₂, and—CO(C₁₋₃ alkyl), wherein the (C₁₋₃ alkyl) is most preferably methyl.

[0091] When the pyrazole ring system is monocyclic, preferred R² groupsinclude hydrogen, C₁₋₄ aliphatic, alkoxycarbonyl, (un)substitutedphenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- ordialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl)carbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃,CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n—C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n—C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

[0092] Preferred Q groups of formula I include —S—, —NH—, and —CH₂—.More preferred Q groups of formula I include —S— and —NH—.

[0093] Another embodiment of this invention relates to compounds offormula II:

[0094] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0095] Z¹ is nitrogen or CR⁸;

[0096] R^(y) is Z—R^(3′) or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms, or R^(y) and R⁸are taken together to form a fused, optionally substituted 5-7 membered,unsaturated or partially unsaturated, ring having 0-3 ring heteroatomsselected from nitrogen, oxygen, or sulfur;

[0097] Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—;

[0098] R¹ is T-(Ring D);

[0099] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0100] T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is—CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is optionallyreplaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—, —SO₂NH—,—NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

[0101] Z is a C₁₋₄ alkylidene chain;

[0102] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0103] R² and R^(2′) are independently selected from —R, -T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0104] R^(3′) is selected from -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, —OC(═O)N(R⁷)₂, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms;

[0105] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0106] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0107] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0108] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—,—N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)——C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or—C(R⁶)₂N(R⁶)CON(R⁶)—;

[0109] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0110] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0111] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0112] R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂; provided that when Q is —NH— and R^(y) andR⁸ are taken together to form a fused ring, R¹ is other than apyrazol-3-yl ring or a pyrazol-3-yl-containing bicyclic ring system.

[0113] Another embodiment of this invention relates to compounds offormula IIa:

[0114] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0115] R^(y) is Z—R^(3′) or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms;

[0116] Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—;

[0117] R¹ is T-(Ring D);

[0118] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0119] T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is—CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is optionallyreplaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—, —SO₂NH—,—NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

[0120] Z is a C₁₋₄ alkylidene chain;

[0121] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0122] R² and R^(2′) are independently selected from —R, -T—W—R or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0123] R^(3′) is selected from -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, —OC(═O)N(R⁷)₂, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms;

[0124] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₁₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0125] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0126] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0127] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, C(R⁶)₂N(R⁶)SO₂N(R⁶) , or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0128] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0129] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0130] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0131] Preferred R^(y) groups of formula IIa include Z—R^(3′) or anoptionally substituted group selected from C₁₋₆ aliphatic, 5-6 memberedheterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is amethylene and R^(3′) is —N(R⁴)₂, —OR, or an optionally substituted groupselected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

[0132] Examples of preferred R^(y) groups include 2-pyridyl, 4-pyridyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such asmethoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl,alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- ordialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionallysubstituted phenyl such as phenyl or halo-substituted phenyl.

[0133] The R² and R^(2′) groups of formula IIa may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIa compounds having apyrazole-containing bicyclic ring system:

[0134] Preferred substituents on the R²/R^(2′) fused ring of formula IIainclude one or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0135] When the pyrazole ring system of formula IIa is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0136] When Ring D of formula IIa is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0137] When Ring D of formula IIa is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0138] On Ring D of formula IIa, preferred T—R⁵ or V—Z—R⁵ substituentsinclude -halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl) , —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0139] Preferred formula IIa compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0140] (a) R^(y) is Z—R^(3′) or an optionally substituted group selectedfrom C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl, wherein Z is a methylene and R^(3′) is —N(R⁴)₂, —OR, or anoptionally substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, aheteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having5-10 ring atoms;

[0141] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0142] (c) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0143] (d) R² is —R or -T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0144] More preferred compounds of formula IIa have one or more, andmore preferably all, of the features selected from the group consistingof:

[0145] (a) R^(y) is an optionally substituted group selected from C₁₋₆aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl;

[0146] (b) R¹ is T-(Ring D), wherein T is a valence bond and Q is —S—,—NH—, or —CH₂—;

[0147] (c) Ring D is a 5-6 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0148] (d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring.

[0149] Even more preferred compounds of formula IIa have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0150] (a) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl;

[0151] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from -halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, and Q is —S— or —NH—; and

[0152] (c) R² is hydrogen or a substituted or unsubstituted C₁₋₆aliphatic, and L is —O—, —S—, or —NH—.

[0153] Representative compounds of formula IIa are shown below inTable 1. TABLE 1 IIa-1

IIa-2

IIa-3

IIa-4

IIa-5

IIa-6

IIa-7

IIa-8

IIa-9

IIa-10

IIa-11

IIa-12

IIa-13

IIa-14

IIa-15

[0154] In another embodiment, this invention provides a compositioncomprising a compound of formula IIa and a pharmaceutically acceptablecarrier.

[0155] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIa or a pharmaceutical composition thereof.

[0156] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IIa or a compositioncomprising said compound.

[0157] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such treatment atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof.

[0158] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0159] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IIa or a compositioncomprising said compound.

[0160] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIa, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0161] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIa, asdescribed above.

[0162] Another embodiment of this invention relates to compounds offormula IIb:

[0163] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0164] R^(y) is Z—R^(3′) or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₁₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms, or R^(y) and R⁸are taken together to form a fused, optionally substituted 5-7 membered,unsaturated or partially unsaturated, ring having 0-3 ring heteroatomsselected from nitrogen, oxygen, or sulfur;

[0165] Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—;

[0166] R¹ is T-(Ring D)

[0167] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0168] T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is—CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is optionallyreplaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—, —SO₂NH—,—NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

[0169] Z is a C₁₋₄ alkylidene chain;

[0170] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0171] R² and R^(2′) are independently selected from —R, -T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0172] R^(3′) is selected from -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, —OC(═O)N(R⁷)₂, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms;

[0173] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0174] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0175] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0176] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0177] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0178] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0179] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0180] R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂; provided that when Q is —NH— and R^(y) andR⁸ are taken together to form a fused ring, R¹ is other than apyrazol-3-yl ring or a pyrazol-3-yl-containing bicyclic ring system.

[0181] Preferred R^(y) groups of formula IIb include Z—R^(3′) or anoptionally substituted group selected from C₁₋₆ aliphatic, 5-6 memberedheterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is amethylene and R^(3′) is —N(R⁴)₂, —OR, or an optionally substituted groupselected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms..

[0182] Examples of preferred R^(y) groups include 2-pyridyl, 4-pyridyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl,cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such asmethoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl,alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- ordialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionallysubstituted phenyl such as phenyl or halo-substituted phenyl.

[0183] The R² and R^(2′) groups of formula IIb may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIb compounds having apyrazole-containing bicyclic ring system:

[0184] Preferred substituents on the R²/R^(2′) fused ring of formula IIbinclude one or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0185] When the pyrazole ring system of formula IIb is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R² group is hydrogen.

[0186] When Ring D of formula IIb is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0187] When Ring D of formula IIb is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0188] On Ring D of formula IIb, preferred T—R⁵ or V—Z—R⁵ substituentsinclude -halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0189] When R^(y) and R⁸ are taken together to form a fused ring,preferred rings formed by R^(y) and R⁸ include 5-6 membered unsaturatedor partially unsaturated rings having 0-2 heteroatoms. More preferredfused rings formed by R^(y) and R⁸ include benzo, cyclohexo, and pyrido.

[0190] Preferred R⁸ groups of formula IIb, when present, include R, OR,and N(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

[0191] Preferred formula IIb compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0192] (a) R^(y) is Z—R^(3′) or an optionally substituted group selectedfrom C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl, wherein Z is a methylene and R^(3′) is —N(R⁴)₂, —OR, or anoptionally substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, aheteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having5-10 ring atoms;

[0193] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0194] (c) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0195] (d) R² is —R or -T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0196] More preferred compounds of formula IIb have one or more, andmore preferably all, of the features selected from the group consistingof:

[0197] (a) R^(y) is an optionally substituted group selected from C₁₋₆aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl;

[0198] (b) R¹ is T-(Ring D), wherein T is a valence bond, and Q is —S—,—NH—, or —CH₂—;

[0199] (c) Ring D is a 5-6 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0200] (d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring.

[0201] Even more preferred compounds of formula IIb have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0202] (a) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl, or R^(y) and R⁸ are taken togetherto form a 5-6 membered unsaturated or partially unsaturated ring having0-2 heteroatoms selected from nitrogen, oxygen, or sulfur;

[0203] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from -halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, and Q is —S— or —NH—; and

[0204] (c) R² is hydrogen or a substituted or unsubstituted C₁₋₆aliphatic, and L is —O—, —S—, or —NH—.

[0205] Representative compounds of formula IIb are shown below in Table2. TABLE 2 IIb-1

IIb-2

IIb-3

IIb-4

IIb-5

IIb-6

IIb-7

IIb-8

IIb-9

IIb-10

IIb-11

IIb-12

IIb-13

IIb-14

IIb-15

[0206] In another embodiment, this invention provides a compositioncomprising a compound of formula IIb and a pharmaceutically acceptablecarrier.

[0207] Another aspect of this invention relates to a 5 method oftreating or preventing an Aurora-2-mediated disease with an Aurora-2inhibitor, which method comprises administering to a patient in need ofsuch a treatment a therapeutically effective amount of a compound offormula IIb or a pharmaceutical composition thereof.

[0208] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IIb or a compositioncomprising said compound.

[0209] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIb or apharmaceutical composition thereof.

[0210] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIb or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0211] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IIb or a compositioncomprising said compound.

[0212] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIb, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0213] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIb, asdescribed above.

[0214] Another embodiment of this invention relates to compounds offormula III:

[0215] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0216] Z¹ is nitrogen or CR⁸, Z² is nitrogen or CH, and Z³ is nitrogenor CR^(x), provided that one of Z¹ and Z³ is nitrogen;

[0217] R^(x) is T—R³ or L-Z—R³;

[0218] Q is selected from —N(R⁴)—, —O—, —S—, or —CH (R⁶)—;

[0219] R¹ is T-(Ring D);

[0220] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0221] T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is—CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is optionallyreplaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂, —SO₂NH—,—NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

[0222] Z is a C₁₋₄ alkylidene chain;

[0223] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0224] R² and R^(2′) are independently selected from —R, -T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0225] R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic) ,—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0226] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₁₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0227] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0228] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0229] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶ )CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0230] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶ )N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0231] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0232] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0233] R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

[0234] Accordingly, the present invention relates to compounds offormula IIIa, IIIb, IIIc and IIId as shown below:

[0235] Preferred R^(x) groups of formula III include T—R³ wherein T is avalence bond or a methylene and R³ is CN, —R, or —OR. When R³ is —R,preferred R³ groups include an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, or a 5-6 membered heteroaryl orheterocyclyl ring. When R³ is —OR, preferred R groups include anoptionally substituted group C₁₋₆ aliphatic group such as alkyl- ordialkylaminoalkyl and aminoalkyl. Examples of preferred R^(x) includeacetamido, CN, piperidinyl, piperazinyl, phenyl, pyridinyl,imidazol-1-yl, imidazol-2-yl, cyclohexyl, cyclopropyl, methyl, ethyl,isopropyl, t-butyl, NH₂CH₂CH₂NH, and NH₂CH₂CH₂O.

[0236] Preferred R⁸ groups of formula III, when present, include R, OR,and N(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

[0237] The R² and R^(2′) groups of formula III may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula III compounds having apyrazole-containing bicyclic ring system:

[0238] Preferred substituents on the formula III R²/R^(2′) fused ringinclude one or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0239] When the pyrazole ring system of formula III is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R² group is hydrogen.

[0240] When Ring D of formula III is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0241] When Ring D of formula III is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0242] On Ring D of formula III, preferred T—R⁵ or V—Z—R⁵ substituentsinclude -halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CON(R⁴)₂, —OCO(R⁴)₂, —N(R⁴)COR, —N(R⁴)CO₂R,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0243] Preferred compounds of formula IIIa, IIIb, IIIc, or IIId have oneor more, and more preferably all, of the features selected from thegroup consisting of:

[0244] (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group;

[0245] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0246] (c) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0247] (d) R² is —R or -T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0248] More preferred compounds of formula IIIa, IIIb, IIIc, or IIIdhave one or more, and more preferably all, of the features selected fromthe group consisting of:

[0249] (a) R¹ is T-(Ring D), wherein T is a valence bond, and Q is —S—,—NH—, or —CH₂—;

[0250] (b) Ring D is a 5-6 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0251] (c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring.

[0252] Even more preferred compounds of formula IIIa, IIIb, IIIc, orIIId have one or more, and more preferably all, of the features selectedfrom the group consisting of:

[0253] (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl,isopropyl, methylamino or acetimido;

[0254] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from -halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CON(R⁴)₂, —OCO(R⁴)₂, —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, and Q is —S— or —NH—; and

[0255] (c) R² is hydrogen or a substituted or unsubstituted C₁₋₆aliphatic.

[0256] Representative compounds of formula III are shown below in Table3. TABLE 3 III-1

III-2

III-3

III-4

III-5

III-6

III-7

III-8

III-9

III-10

III-11

III-12

III-13

III-14

III-15

III-16

III-17

III-18

III-19

III-20

III-21

III-22

III-23

III-24

III-25

III-26

III-27

III-28

III-29

III-30

[0257] In another embodiment, this invention provides a compositioncomprising a compound of formula III and a pharmaceutically acceptablecarrier.

[0258] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIII or a pharmaceutical composition thereof.

[0259] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula III or a compositioncomprising said compound.

[0260] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula III or apharmaceutical composition thereof.

[0261] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula III or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0262] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula III or a compositioncomprising said compound.

[0263] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula III, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0264] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula III asdescribed above.

[0265] The compounds of this invention may be prepared in general bymethods known to those skilled in the art for analogous compounds, asillustrated by the general Schemes I-VII.

[0266] Scheme I above shows a general route for the preparation ofcompounds of formula IIb. The dichloro intermediate 1 (prepared usingmethods similar to those reported in J. Indian. Chem. Soc., 61, 690-693(1984) or in J. Med. Chem., 37, 3828-3833 (1994)) is sequentiallyreacted with two nucleophiles: R¹-QH to displace the chloride atposition 4 to afford intermediate 2; and then 2 is treated with anaminopyrazole (or aminoindazole) to displace the chloride at position 2,using procedures similar to those described in J. Med. Chem, 38, 14,2763-2773, (1995) to afford compounds of formula IIb.

[0267] Scheme II above shows a general route for the preparation ofcompounds of formula IIb wherein Q is an N, O or S linker and R^(y) is agroup attached to the pyrimidine core via a heteroatom. Startingmaterial 4,6-dihydroxy-2-methylsulfanylpyrimidine (4) is prepared usingprocedures similar to those reported in J. Med. Chem., 27, 12, 1621-1629(1984). Chlorination of 4 with POCl₃ affords the dichloro intermediate5. The two chlorides of 5 are sequentially displaced with theappropriate R¹-QH, to afford compound 6, and then with R^(y)-H (amine,alcohol, or thiol) to afford compound 7 using procedures similar tothose reported in U.S. Pat. No. 2,585,906. Alternatively, the order ofdisplacement may be reversed by first displacing with R^(y)-H and thenwith R¹-QH. The methyl sulfanyl group of compound 7 is then oxidized(for example, with oxone) to afford compound 8 and the resultingmethylsulfonyl is finally displaced with the amino moiety ofaminopyrazole (or aminoindazole) by methods substantially similar tothose described above for Scheme 1 step (b) to afford compounds offormula IIb.

[0268] Scheme III above shows a general route for the preparation ofcompounds of formula IIa. The three chlorides of starting material 8 aresequentially displaced with (a) the amino moiety of aminopyrazole (oraminoindazole) to afford compound 9, (b) the R¹-QH group to affordcompound 10, and (c) R^(y)-H (amine, alcohol, or thiol) using proceduressimilar to the ones reported in J. Indian Chem. Soc., 53, 207-208,(1976) to afford compounds of formula IIa. These three steps can also beperformed in different order to afford compounds of formula IIa.

[0269] Scheme IV above shows a general route for the preparation ofcompounds of formula IIIa. Treatment of 11 with aminopyrazole (oraminoindazole) to provide 12 may be performed in a manner similar tothat described in Heterocycles, 51, 5, 1999, 1035-1050. The intermediate13 is obtained by displacement with R¹-QH in a manner similar to thatdescribed in Farmaco. Ed. Sci., 27, 1972, 591-600. For the preparationof compounds of formula IIIa where R^(x) is hydrogen, the chlorine maybe removed by reduction. Alternatively, for the preparation of compoundsof formula IIIa where R^(x) is other than hydrogen, the chlorine may bedisplaced by methods known to those skilled in the art to affordcompounds with a variety of R^(x) substituents.

[0270] Scheme V above shows a general route for the preparation of thecompounds of formula IIIb. Displacement of the bromide with R¹-QH toafford compound 15 may be performed in a manner similar to thatdescribed in Heterocycles, 51, 5, 1999, 1035-1050. Displacement of thechlorines may be carried out sequentially as described above.

[0271] Scheme VI above shows a general route for the preparation of thecompounds of formulae IIIc and IIId. The displacement with aminopyrazole(or aminoindazole) followed by the displacement with R¹-QH may beperformed in a manner similar to that described in Indian J. Chem. Sect.B, 29, 5, 1990, 435-439.

[0272] In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

BIOLOGICAL TESTING

[0273] The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of the activated protein kinase. Alternate in vitroassays quantitate the ability of the inhibitor to bind to the proteinkinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor/protein kinasecomplex and determining the amount of radiolabel bound. Alternatively,inhibitor binding may be determined by running a competition experimentwhere new inhibitors are incubated with the protein kinase bound toknown radioligands.

BIOLOGICAL TESTING EXAMPLE 1 K_(i) Determination for the Inhibition ofGSK-3

[0274] Compounds are screened for their ability to inhibit GSK-3β (AA1-420) activity using a standard coupled enzyme system (Fox et al.(1998) Protein Sci. 7, 2249). Reactions are carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay are20 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide(HSSPHQS(PO₃H₂)EDEEE, American Peptide, Sunnyvale, Calif.). Reactionsare carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system are 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

[0275] An assay stock buffer solution is prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. The assay stock buffer solution (175 μl) is incubated in a 96well plate with 5 μl of the test compound of interest at finalconcentrations spanning 0.002 μM to 30 μM at 30° C. for 10 min.Typically, a 12 point titration is conducted by preparing serialdilutions (from 10 mM compound stocks) with DMSO of the test compoundsin daughter plates. The reaction is initiated by the addition of 20 μlof ATP (final concentration 20 μM). Rates of reaction are obtained usinga Molecular Devices Spectramax plate reader (Sunnyvale, Calif.) over 10min at 30° C. The K_(i) values are determined from the rate data as afunction of inhibitor concentration.

BIOLOGICAL TESTING EXAMPLE 2 K_(i) Determination for the Inhibition ofAurora-2

[0276] Compounds are screened in the following manner for their abilityto inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al(1998) Protein Sci 7, 2249).

[0277] To an assay stock buffer solution containing 0.1M HEPES 7.5, 10mM MgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH,30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and800 μM peptide (LRRASLG, American Peptide, Sunnyvale, Calif.) is added aDMSO solution of a compound of the present invention to a finalconcentration of 30 μM. The resulting mixture is incubated at 30° C. for10 min. The reaction is initiated by the addition of 10 μL of Aurora-2stock solution to give a final concentration of 70 nM in the assay. Therates of reaction are obtained by monitoring absorbance at 340 nm over a5 minute read time at 30° C. using a BioRad Ultramark plate reader(Hercules, Calif.). The K_(i) values are determined from the rate dataas a function of inhibitor concentration.

[0278] While we have presented a number of embodiments of thisinvention, it is apparent that our basic construction can be altered toprovide other embodiments which utilize the compounds and methods ofthis invention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments which have been represented by way of example.

We claim:
 1. A compound of formula III:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:Z¹ is nitrogen or CR⁸, Z² is nitrogen or CH, and Z³ is nitrogen orCR^(x), provided that one of Z¹ and Z³ is nitrogen; R^(x) is T—R³ orL-Z—R³; Q is selected from —N(R⁴)—, —O—, —S—, or —CH(R⁶)—; R¹ is T-(RingD); Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclicring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴; T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is—CH(R⁶)—, a methylene unit of said C₁₋₄ alkylidene chain is optionallyreplaced by —O—, —S—, —N(R⁴)—, —CO—, ——OC(O)NH—, or —NHCO₂—; Z is a C₁₋₄alkylidene chain; L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—,—N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—,—N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—,—C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)——C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or—C(R⁶)₂N(R⁶)CON(R⁶)—; R² and R^(2′) are independently selected from —R,-T—W—R⁶, or R² and R^(2′) are taken together with their interveningatoms to form a fused, 5-8 membered, unsaturated or partiallyunsaturated, ring having 0-3 ring heteroatoms selected from nitrogen,oxygen, or sulfur, wherein each substitutable ring carbon of said fusedring formed by R² and R^(2′) is independently substituted by halo, oxo,—CN, —NO₂, —R⁷, or —V—R , and each substitutable ring nitrogen of saidring formed by R² and R^(2′) is independently substituted by R⁴; R³ isselected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR, —NO₂,—CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R,—N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂; each R isindependently selected from hydrogen or an optionally substituted groupselected from C₁₋₆ aliphatic, C₁₋₁₀ aryl, a heteroaryl ring having 5-10ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R⁴ isindependently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆aliphatic), —CON(R⁷)₂, or —SO₂R⁷; each R⁵ is independently selected from—R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂; V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶),—N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—,—N(R⁶)SO₂N(R⁶), —N(R⁶)N(R⁶), —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—,—C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R)—; W is—C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—; each R⁶ is independently selected from hydrogen or anoptionally substituted C₁₋₄ aliphatic group, or two R⁶ groups on thesame nitrogen atom are taken together with the nitrogen atom to form a5-6 membered heterocyclyl or heteroaryl ring; each R⁷ is independentlyselected from hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, or two R⁷ on the same nitrogen are taken together with thenitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R⁸is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂.
 2. The compound according to claim 1, wherein Q is—N(R⁴)—, —S—, or —CH(R⁶)—, and said compound is of formula IIIa, IIIb,IIIc, or IIId:

or a pharmaceutically acceptable derivative or prodrug thereof.
 3. Thecompound according to claim 2, wherein said compound has one or morefeatures selected from the group consisting of: (a) R^(x) is hydrogen,alkyl- or dialkylamino, acetamido, or a C₁₋₄ aliphatic group; (b) R¹ isT-(Ring D), wherein T is a valence bond or a methylene unit; (c) Ring Dis a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl orheteroaryl ring; and (d) R² is —R or -T—W—R⁶ and R^(2′) is hydrogen, orR² and R^(2′) are taken together to form an optionally substituted benzoring.
 4. The compound according to claim 3, wherein: (a) R^(x) ishydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄ aliphatic group;(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring; and (d) R² is —R or -T—W—R⁶ and R^(2′) ishydrogen, or R² and R^(2′) are taken together to form an optionallysubstituted benzo ring.
 5. The compound according to claim 3, whereinsaid compound has one or more features selected from the groupconsisting of: (a) R¹ is T-(Ring D), wherein T is a valence bond, and Qis —S— or —NH—; (b) Ring D is a 5-6 membered monocyclic or an 8-10membered bicyclic aryl or heteroaryl ring; and (c) R² is —R and R^(2′)is hydrogen, wherein R is selected from hydrogen, C₁₋₆ aliphatic,phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclicring.
 6. The compound according to claim 5, wherein: (a) R¹ is T-(RingD), wherein T is a valence bond, and Q is —S— or —NH—; (b) Ring D is a5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroarylring; and (c) R² is —R and R^(2′) is hydrogen, wherein R is selectedfrom hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring,or a 5-6 membered heterocyclic ring.
 7. The compound according to claim5, wherein said compound has one or more features selected from thegroup consisting of: (a) R^(x) is hydrogen methyl, ethyl, propyl,cyclopropyl, isopropyl, methylamino or acetamido; (b) R¹ is T-(Ring D),wherein T is a valence bond and Ring D is a 5-6 membered aryl orheteroaryl ring, wherein Ring D is optionally substituted with one totwo groups selected from -halo, —CN, —NO₂, —N(R⁴)₂, optionallysubstituted C₁₋₆ aliphatic group, —OR, —CO₂R, —CON(R⁴)₂, —OCO(R⁴)₂,—N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;and (c) R² is hydrogen or a substituted or unsubstituted C₁₋₆ aliphatic.8. The compound according to claim 7, wherein: (a) R^(x) is hydrogenmethyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido;(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from -halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CON(R⁴)₂, —OCO(R⁴)₂, —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂; and (c) R² is hydrogen or a substituted orunsubstituted C₁₋₆ aliphatic.
 9. A compound selected from the groupconsisting of:N⁵-(1H-Indazol-6-yl)—N³-(5-methyl-1H-pyrazol-3-yl)-[1,2,4]triazine-3,5-diamine;N-{4-[3-(5-Methyl-1H-pyrazol-3-ylamino)-[1,2,4]triazin-5-ylsulfanyl]-phenyl}-acetamide;[5-(3-Methoxy-benzyl)-[1,2,4]triazin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine;N³-(5—Cyclopropyl-1H-pyrazol-3-yl)-N⁵-pyridin-3-ylmethyl-[1,2,4]triazine-3,5-diamine;[5-(Benzothiazol-6-ylsulfanyl)-[1,2,4]triazin-3-yl]-(5-cyclopropyl-1H-pyrazol-3-yl)-amine;{4-[3-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-[1,2,4]triazin-5-yloxy]-phenyl}-acetonitrile;N-{4-[3-(1H-Indazol-3-ylamino)-[1,2,4]triazin-5-ylamino]-phenyl}-methanesulfonamide;(1H-Indazol-3-yl)-[5-(thiophen-2-ylmethylsulfanyl)-[1,2,4]triazin-3-yl]-amine;N⁵-(5-Methyl-1H-pyrazol-3-yl)-N³-pyridin-3-ylmethyl-[1,2,4]triazine-3,5-diamine;[3-(Benzothiazol-6-ylsulfanyl)-[1,2,4]triazin-5-yl]-(5-methyl-1H-pyrazol-3-yl)-amine;{4-[5-(5-Methyl-1H-pyrazol-3-ylamino)-[1,2,4]triazin-3-yloxy]-phenyl}-acetonitrile;N⁵-(5-Cyclopropyl-1H-pyrazol-3-yl)-N³-(1H-indazol-6-yl)-[1,2,4]triazine-3,5-diamine;N-{4-[5-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-[1,2,4]triazin-3-ylsulfanyl]-phenyl}-acetamide;N⁵-(1H-Indazol-3-yl)-N³-(1H-indazol-6-yl)-[1,2,4]triazine-3,5-diamine;(1H-Indazol-3-yl)-[3-(3-methoxy-phenylsulfanyl)-[1,2,4]triazin-5-yl]-amine;N⁵-(1H-Indazol-6-yl)-N³-(5-methyl-1H-pyrazol-3-yl)-pyridazine-3,5-diamine;N-{4-[6-(5-Methyl-1H-pyrazol-3-ylamino)-pyridazin-4-ylsulfanyl]-phenyl}-acetamide;[5-(3-Methoxy-benzyl)-pyridazin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine;N³-(5-Cyclopropyl-1H-pyrazol-3-yl)-N⁵-pyridin-3-ylmethyl-pyridazine-3,5-diamine;[5-(Benzothiazol-6-ylsulfanyl)-pyridazin-3-yl]-(5-cyclopropyl-1H-pyrazol-3-yl)-amine;{4-[6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-pyridazin-4-yloxy]-phenyl}-acetonitrile;N-{4-[6-(1H-Indazol-3-ylamino)-pyridazin-4-ylamino]-phenyl}-methanesulfonamide;(1H-Indazol-3-yl)-[5-(thiophen-₂-ylmethylsulfanyl)-pyridazin-3-yl]-amine;N⁵-(5-Methyl-1H-pyrazol-3-yl)-N³-pyridin-3-ylmethyl-pyridazine-3,5-diamine;[6-(Benzothiazol-6-ylsulfanyl)-pyridazin-4-yl]-(5-methyl-1H-pyrazol-3-yl)-amine;{4-[5-(5-Methyl-1H-pyrazol-3-ylamino)-pyridazin-3-yloxy]-phenyl}-acetonitrile;N⁵-(5-Cyclopropyl-1H-pyrazol-3-yl)-N³-(1H-indazol-6-yl)-pyridazine-3,5-diamine;N-{4-[5-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-pyridazin-3-ylsulfanyl]-phenyl}-acetamide;N⁵-(1H-Indazol-3-yl)-N³-(1H-indazol-6-yl)-pyridazine-3,5-diamine; and(1H-Indazol-3-yl)-[6-(3-methoxy-phenylsulfanyl)-pyridazin-4-yl]-amine.10. A composition comprising a compound according to any of claims 1-9,and a pharmaceutically acceptable carrier.
 11. The composition accordingto claim 10, further comprising an additional therapeutic agent.
 12. Amethod of inhibiting Aurora-2 or GSK-3 activity in a biological samplecomprising the step of contacting said biological sample with a compoundaccording to any one of claims 1-9.
 13. A method of inhibiting Aurora-2activity in a patient comprising the step of administering to saidpatient a composition according to claim
 10. 14. A method of inhibitingAurora-2 activity in a patient comprising the step of administering tosaid patient a composition according to claim
 11. 15. A method oftreating an Aurora-2-mediated disease, which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a composition according to claim
 10. 16. The methodaccording to claim 15, wherein said disease is selected from colon,breast, stomach, or ovarian cancer.
 17. The method according to claim16, wherein said method further comprises administering an additionaltherapeutic agent.
 18. The method according to claim 17, wherein saidadditional therapeutic agent is a chemotherapeutic agent.
 19. A methodof inhibiting GSK-3 activity in a patient comprising the step ofadministering to said patient a composition according to claim
 10. 20. Amethod of inhibiting GSK-3 activity in a patient comprising the step ofadministering to said patient a composition according to claim
 11. 21. Amethod of method of treating a GSK-3-mediated disease, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a composition according to claim 10.22. The method according to claim 21, wherein said GSK-3-mediateddisease is selected from diabetes, Alzheimer's disease, Huntington'sDisease, Parkinson's Disease, AIDS-associated dementia, amyotrophiclateral sclerosis (AML), multiple sclerosis (MS), schizophrenia,cardiomycete hypertrophy, reperfusion/ischemia, or baldness.
 23. Themethod according to claim 22, wherein said GSK-3-mediated disease isdiabetes.
 24. A method of enhancing glycogen synthesis or lowering bloodlevels of glucose in a patient in need thereof, which method comprisesadministering to said patient a therapeutically effective amount of acomposition according to claim
 10. 25. A method of inhibiting theproduction of hyperphosphorylated Tau protein in a patient, which methodcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a composition according to claim
 10. 26. A method ofinhibiting the phosphorylation of β-catenin, which method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a composition according to claim 10.